The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
Phosphoinositide 3-Kinase Catalytic Subunit Deletion and Regulatory Subunit Deletion Have Opposite Effects on Insulin Sensitivity in Mice
Open accessAbstract
Studies ex vivo have shown that phosphoinositide 3-kinase (PI3K) activity is necessary but not sufficient for insulin-stimulated glucose uptake. Unexpectedly, mice lacking either of the PI3K regulatory subunits p85alpha or p85beta exhibit increased insulin sensitivity. The insulin hypersensitivity is particularly unexpected in p85alpha-/- p55alpha-/- p50alpha-/- mice, where a decrease in p110alpha and p110beta catalytic subunits was observed in insulin-sensitive tissues. These results raised the possibility that decreasing total PI3K available for stimulation by insulin might circumvent negative feedback loops that ultimately shut off insulin-dependent glucose uptake in vivo. Here we present results arguing against this explanation. We show that p110alpha+/- p110beta+/- mice exhibit mild glucose intolerance and hyperinsulinemia in the fasted state. Unexpectedly, p110alpha+/- p110beta+/- mice showed a approximately 50% decrease in p85 expression in liver and muscle. Consistent with this in vivo observation, knockdown of p110 by RNA interference in mammalian cells resulted in loss of p85 proteins due to decreased protein stability. We propose that insulin sensitivity is regulated by a delicate balance between p85 and p110 subunits and that p85 subunits mediate a negative role in insulin signaling independent of their role as mediators of PI3K activation.
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Cites
A central role for JNK in obesity and insulin resistance
Hirosumi, J., Tuncman, G., Chang, L., Görgün, C. Z., Uysal, K. T., Maeda, K., Karin, M., & Hotamisligil, G. S. (2002) · Nature · doi:10.1038/nature01137 · Cited by 3,359
Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity
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Insulin resistance as the core defect in type 2 diabetes mellitus
Goldstein, B. J. (2002) · The American Journal of Cardiology · doi:10.1016/s0002-9149(02)02553-5 · Cited by 432
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Engelman, J. A., Luo, J., & Cantley, L. C. (2006) · Nature Reviews Genetics · doi:10.1038/nrg1879 · Cited by 3,330
Self-citationMechanisms of Insulin Action and Insulin Resistance
Petersen, M. C., & Shulman, G. I. (2018) · Physiological Reviews · doi:10.1152/physrev.00063.2017 · Cited by 3,028
Targeting the phosphoinositide 3-kinase pathway in cancer
Liu, P., Cheng, H., Roberts, T. M., & Zhao, J. J. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2926 · Cited by 2,721
Engelman, J. A., Chen, L., Tan, X., Crosby, K., Guimaraes, A. R., Upadhyay, R., Maira, M., McNamara, K., Perera, S. A., Song, Y., et al. (2008) · Nature Medicine · doi:10.1038/nm.1890 · Cited by 1,330
Self-citationA Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling
Knight, Z. A., Gonzalez, B., Feldman, M. E., Zunder, E. R., Goldenberg, D. D., Williams, O., Loewith, R., Stokoe, D., Balla, A., Toth, B., et al. (2006) · Cell · doi:10.1016/j.cell.2006.03.035 · Cited by 1,174
Metadata
- Authors
- Brachmann, S. M., Ueki, K., Engelman, J. A., Kahn, R. C., & Cantley, L. C.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2005-03
- Volume
- 25
- Issue
- 5
- Pages
- 1596-1607
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2137618229
- Cited by
- 179
- References
- 10
- FWCI
- 5.53
- Type
- journal article
- Language
- en
- Open access
- green
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- Brachmann, S. M., Ueki, K., Engelman, J. A., Kahn, R. C., & Cantley, L. C. (2005). Phosphoinositide 3-Kinase Catalytic Subunit Deletion and Regulatory Subunit Deletion Have Opposite Effects on Insulin Sensitivity in Mice. Molecular and Cellular Biology. https://doi.org/10.1128/mcb.25.5.1596-1607.2005
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